Journal of Natural Products
ARTICLE
bromide (20.1 mmol; 6.7 mL of 3 M in ether) was added dropwise,
maintaining the temperature from ꢀ27 to ꢀ30 °C. At the end of the
addition a sticky precipitate was formed, and stirring was continued at
ꢀ30 °C for 1 h. The reaction mixture was poured into an ice-cold
saturated ammonium chloride solution, acidified with 1 M HCl to pH 6,
and extracted with hexane. Combined hexane extracts were washed four
times with water, dried, and evaporated, and the residue was chromato-
graphed with hexane, then hexane/ethyl acetate, 5:1. Hydrocarbon 4
(2.27 g, 84%) was isolated as a 53:47 mixture of two diastereoisomers
baseline separated on a HP-5MS column. The first eluted peak matched
7-epi-sesquithujene isolatedfrom phoebeoil bythe massspectrum and the
retention time. GC analysis on a HYDRODEX β-6TBDM column
showed that 4 consisted of 48% 1, 6% (ꢀ)-7-epi-sesquithujene (16),
41% (ꢀ)-sesquithujene, and 5% (þ)-sesquithujene (17). Unreacted 3
(560 mg, 12%) was also isolated from the second fraction.
Methylation of Triflate 6. A solution of triflate 6 (433 mg, 1.28
mmol), N-methyl-2-pyrrolidone (1.4 mL), and iron(III) acetylacetonate
(45 mg, 0.13 mmol, 10% of 6) in dry THF (30 mL) was treated at
ꢀ30 °C with methylmagnesium bromide (1.54 mmol; 512 μL of 3 M in
ether). After the workup described above and flash chromatography with
1% ethyl acetate in hexane, 7 (60 mg, 61%) was isolated as a mixture of
16 (51%), 1 (1%), (ꢀ)-sesquithujene (1%), and 17 (46%). Unreacted 6
(108 mg, 25%) was also recovered.
L-Selectride Reduction of Ketone 5. A procedure by Mori
et al12 was followed. L-Selectride (LiB(sec-Bu)3H, 4.18 mmol; 4.18 mL
of 1.0 M in THF) was added to a solution of ketone 5 (840 mg, 4.08
mmol) in dry THF (20 mL) at ꢀ65 °C. The mixture was slowly warmed
to ꢀ20 °C within 3 h, upon which the reduction was completed as
judged by TLC analysis. A 3 M solution of NaOH (12.2 mL) was added
at ꢀ20 °C followed by hydrogen peroxide (460 μL of 50% solution),
which caused the reaction temperature to rise to 0 °C. The mixture was
stirred at that temperature for 2 h, then diluted with H2O (∼10 mL) and
extracted three times with hexane/ether, 1:1. The combined organic
extracts were washed with an ammonium chloride solution and brine
and then dried. Flash chromatography gave three fractions:
br dd, J = 4.2), 0.90 (1.5H, d, J = 6.6), 0.93 (1.5H, d, J = 6.6), 1.10 (2H, m),
1.18ꢀ1.33 (2H, m), 1.37ꢀ1.47 (2H, m), 1.58ꢀ1.68 (2H, m), 1.61 (3H,
br s), 1.69 (3H, br s), 1.89ꢀ2.03 (3H, m), 4.52 (1H, br m, H-3), 5.10
(1H, tm, J = 7.2); 13C NMR, δ 9.57, 11.58, 17.71, 17.81, 17.88, 25.03,
25.49, 25.91, 26.33, 26.41, 28.05, 29.40, 30.01, 30.15, 33.23, 33.28,
34.83, 35.00, 37.89, 37.97, 74.66, 74.76, 125.05, 125.10, 131.41, 131.47.
Some of these peaks corresponded to composite signals from carbons in
both diastereomers. HREIMS m/z 208.1825 (calcd for C14H24O,
208.1827).
Ketone 12. (Diacetoxyiodo)benzene (215 mg, 0.67 mmol) was
added to a stirred solution of alcohol 10 (126 mg, 0.61 mmol) and
2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO, 9.4 mg, 0.06 mmol) in a
mixture of pentane (0.4 mL) and CH2Cl2 (0.6 mL).14 The mixture was
stirred at 25 °C for 1 h, diluted with CH2Cl2 (5 mL), and washed with a
saturated Na2S2O3 solution (2 mL). Then the aqueous layer was
extracted with CH2Cl2 (4 ꢁ 1 mL). The combined organic extracts
were washed with a saturated NaHCO3 solution to pH 8, then with
brine, and dried. After evaporation of the solvent and flash chromatog-
raphy with CH2Cl2, ketone 12 was isolated (101 mg, 80%). Compound
12 was 95% pure by GC-MS and contained 4% of 13: [R]25 ꢀ20.8
D
(c 3.35, CH2Cl2) [lit.10 for (2R,6S,7R)-12 [R]20 þ16.2 (c 1.62,
D
CH2Cl2)]; GC-EIMS m/z 206 [M]þ (14), 191 (8), 188 (5), 163
(25), 149 (21), 136 (25), 123 (91), 121 (53), 109 (36), 95 (40), 93 (44),
82 (56), 79 (50), 69 (100), 67 (65), 55 (78), 41 (82); 1H NMR, δ 0.98
(3H, d, J = 6.5), 1.08 (1H, dd, J = 4.6, 3.1, endo-H-1), 1.13 (1H, br dd,
J = 9.1, 4.6, exo-H-1), 1.33 (2H, m), 1.50 (1H, m), 1.60 (3H, br s), 1.67
(1H, dd, J = 9.1, 3.1, H-2), 1.69 (3H, br s), 1.90ꢀ2.17 (6H, m), 5.06 (1H,
tm, J = 7.0); 13C NMR, δ 17.0, 17.8, 19.3, 23.4, 25.7, 25.8, 33.1, 34.3,
34.5, 37.2, 38.8, 124.2, 131.7, 214.7. 1H and 13C NMR data were in good
agreement with those reported in the literature for (2R,6S,7R)-12.10
Ketone 13. Alcohol 11 (67 mg, 0.32 mmol) was oxidized with
PhI(OAc)2 (114 mg, 0.35 mmol) in the presence of TEMPO (2.5 mg,
0.02 mmol) in a pentane/CH2Cl2 solution (0.2 mL þ 0.3 mL) to give
ketone 13 of 2R,6S,7S configuration (55 mg, 83%, 98% pure): [R]25
þ28.0 (c 2.75, CH2Cl2) [lit.10 for (2S,6R,7R)-13 [R]20 ꢀ27.2 (c
D
D
1.36, CH2Cl2)]; GC-EIMS m/z 206 [M]þ (12), 191 (6), 188 (4), 163
(25), 149 (17), 136 (21), 123 (71), 121 (42), 109 (32), 95 (35), 93 (41),
82 (52), 79 (46), 69 (100), 67 (60), 55 (77), 41 (80); 1H NMR, δ 0.99
(3H, d, J = 6.6), 1.16 (1H, dd, J = 4.2, 3.6, endo-H-1), 1.19 (1H, br dd, J =
9.0, 4.2, exo-H-1), 1.28 (1H, m), 1.32 (1H, m), 1.45 (1H, m), 1.59 (1H,
m), 1.62 (3H, br s), 1.70 (3H, br s), 1.90 (1H, dd, J = 11.4, 8.9),
1.98ꢀ2.19 (5H, m), 5.09 (1H, tm, J = 7.2); 13C NMR, δ 17.5, 17.7, 21.4,
22.5, 25.7, 26.0, 33.2, 33.4, 34.2, 37.4, 38.9, 124.3, 131.7, 214.9. 1H and
13C NMR data were in good agreement with those reported in the
literature for (2S,6R,7R)-13.10
No. 1: Alcohol 10 of 2S,3S,6R,7S configuration (89 mg, 97%-pure):
Rf = 0.34, hexane/ethyl acetate, 3:1; [R]25 ꢀ9.53 (c 1.50, CH2Cl2);
D
GC-EIMS m/z 190 (9), 175 (5), 147 (17), 123 (52), 109 (33), 107 (26),
105 (53), 93 (37), 82 (100), 79 (56), 69 (82), 67 (41), 55 (43), 41 (57);
1H NMR, δ 0.21 (1H, dd, J = 4.9, 3.6, endo-H-1), 0.34 (1H, br dd, J = 8.4,
5.1, exo-H-1), 0.95 (3H, d, J = 6.6), 1.16 (1H, br dd, J = 8.4, 3.6, H-2), 1.21
(1H, m), 1.29ꢀ1.37 (2H, m), 1.37ꢀ1.44 (1H, m), 1.47ꢀ1.53 (1H, m),
1.53ꢀ1.60 (2H, m), 1.61 (3H, br s), 1.69 (3H, br s), 1.82 (1H m), 2.03
(2H, m), 4.19 (1H, br d, J = 4.8, H-3), 5.11 (1H, br t, J = 7.2); 13C NMR,
δ 13.1, 17.9, 18.3, 24.9, 25.9, 26.4, 30.9, 31.6, 34.1, 35.06, 37.4, 75.2,
125.2, 131.4; HREIMS m/z 208.1825 (calcd for C14H24O, 208.1827).
No. 2: Alcohol 11 of 2R,3R,6S,7S configuration (67 mg, 97% pure):
Triflate 14. Analogously to diastereomeric mixture 2, ketone 12 (98
mg, 0.48 mmol) in 2 mL of THF was allowed to react with LDA, formed
from diisopropylamine (112 μL, 0.79 mmol) and butyllithium (0.77
mmol; 425 μL of 1.8 M in hexane). N-(5-Chloro-2-pyridyl)bis-
(trifluoromethanesulfonimide) (300 mg, 0.76 mmol) dissolved in
1 mL of THF was added. After the workup described, triflate 14 (91
mg, 56%) was isolated. 1H NMR, δ 0.49 (1H, dd, J = 4.4, 3.0, endo-H-1),
0.92 (1H, dd, J = 7.2, 4.8, exo-H-1), 0.96 (3H, d, J = 7.2), 1.23 (1H, sextet,
J = 7.2), 1.32 (1H, m), 1.47 (1H, m), 1.60 (3H, br s), 1.69 (3H, br s),
1.75 (1H, m), 1.99 (2H, m), 2.29 (1H, dt, J = 17.4, 3.0), 2.46 (1H, dd, J =
17.4, 2.4), 5.08 (1H, tm, J = 6.6), 5.27 (1H, m); 13C NMR, δ 17.5, 17.6,
21.1, 25.7, 25.9, 26.2, 31.4, 32.1, 34.7, 37.6, 113.5, 124.4, 131.7, 152.6.
One of these signals corresponded to two carbons. HRESIMS m/z
339.1246 (calcd for [M þ H]þ C15H22F3O3S, 339.1242).
Rf = 0.28, hexane/ethyl acetate, 3:1; [R]25 þ0.30 (c 3.35, CH2Cl2);
D
GC-EIMS m/z 208, [M]þ (2), 190 (9), 175 (7), 147 (20), 123 (71), 109
(40), 107 (23), 105 (59), 93 (42), 82 (96), 79 (63), 69 (100), 67 (46),
55 (50), 41 (65); 1H NMR, δ 0.30 (1H, dd, J = 4.8, 3.6, endo-H-1), 0.41
(1H, br dd, J = 8.4, 4.8, exo-H-1), 1.00 (3H, d, J = 6.6), 1.06 (1H, br dd,
J = 8.4, 3.0, H-2), 1.16 (1H, sextet, J = 7.2), 1.28 (2H, m), 1.37ꢀ1.47
(2H, m), 1.50 (1H, m), 1.57 (1H, m), 1.61 (3H, br s), 1.69 (3H, br s),
1.84 (1H, m), 2.03 (2H, q, J = 7.8), 4.18 (1H, br m, H-3), 5.10 (1H, br t,
J = 7.2); 13C NMR, δ 15.1, 17.89, 17.92, 23.9, 25.9, 26.5, 30.0, 31.6, 33.7,
35.9, 37.5, 75.1, 125.2, 131.4; HREIMS m/z 208.1836 (calcd for
C14H24O, 208.1827).
No. 3: A mixture of endo alcohols 8 and 9 (530 mg, ratio ∼1:1): Rf =
0.20, hexane/ethyl acetate, 3:1. Both diastereomers had similar mass
spectra. GC-EIMS m/z 208 [M]þ (2) 190 (10), 175 (6), 165 (6), 147
(21), 123 (70), 109 (38), 107 (23), 105 (71), 93 (40), 82 (74), 79 (65),
69 (100), 67 (45), 55 (52), 41 (40); 1H NMR, δ 0.26 (0.5H, dd, J = 7.2,
4.8), 0.36 (0.5H, dd, J = 7.2, 4.8), 0.70 (0.5H, br dd, J = 4.2), 0.79 (0.5H,
Triflate 15. Ketone 13 was enolized analogously to the above
procedure using LDA formed from diisopropylamine (75 μL, 0.53
mmol) and butyllithium (0.41 mmol; 225 μL of 1.8 M in hexane),
and then the enolate formed reacted with N-(5-chloro-2-pyridyl)-
bis(trifluoromethanesulfonimide) (158 mg, 0.40 mmol) in THF
1419
dx.doi.org/10.1021/np200098z |J. Nat. Prod. 2011, 74, 1414–1420